Trimetrexate Glucuronate

Action and Spectrum

In vitro studies have demonstrated that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) derived from bacterial, protozoan, and mammalian sources. DHFR is an essential enzyme that catalyzes the reduction of intracellular dihydrofolate to tetrahydrofolate, a crucial coenzyme involved in one-carbon transfer reactions. Inhibition of DHFR by trimetrexate results in the depletion of tetrahydrofolate, leading to the suppression of thymidylate biosynthesis (critical for DNA synthesis), inhibition of folate-dependent formyltransferases, and indirect inhibition of purine biosynthesis. These biochemical disruptions interfere with DNA, RNA, and protein synthesis, ultimately causing cell death, particularly in rapidly dividing cells. The spectrum of trimetrexate includes antiprotozoal activity—specifically against Pneumocystis jirovecii, making it effective in treating Pneumocystis pneumonia (PCP) in immunocompromised patients. It also exhibits in vitro antibacterial activity through DHFR inhibition, although it is not widely used clinically for bacterial infections. 

Drug Interaction

Adverse Reaction

fever (8–13%) 

rash or itching (5–13%) 

nausea and vomiting (5–14%) 

confusion (around 3%) 

fatigue (up to 2%) 

neutropenia (30–33%) 

thrombocytopenia (10–15%) 

anemia (7–9%) 

Black Box Warning

For severe potentially life-threatening myelosuppression, mucositis, and hepatotoxicity. These effects are dose-related and require co-administration with leucovorin (folinic acid) to mitigate toxicity. 

Contraindication / Caution

Contraindications: 

Hypersensitivity to trimetrexate or other DHFR inhibitors 

Pregnancy (Category D): Risk of fetal harm 

Severe hepatic or renal impairment without proper monitoring and dose adjustment 

Lack of access to leucovorin (folinic acid) 

Caution: 

Bone marrow suppression or ongoing infection 

Concurrent use with nephrotoxic or hepatotoxic agents 

Frequent CBC, renal, and liver function monitoring is essential 

Use with caution in the elderly or those with poor nutritional status 

Pregnancy / Lactation

Pregnancy consideration: It is assigned under pregnancy category D. Avoid during pregnancy.  

Lactation: No sufficient data is available that shows whether it is excreted in breast milk. Because of the potential risks, it is advised to avoid the treatment for breastfeeding women. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 

• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 

• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women 

• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 

• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 

• Category N: There is no data available for the drug under this category.

Pharmacology

Trimetrexate is a synthetic, non-classical folate antagonist that works by inhibiting dihydrofolate reductase (DHFR), an enzyme essential for converting folic acid to its active form, tetrahydrofolate, which is required for DNA synthesis and cell division. By blocking this process, trimetrexate disrupts the reproduction of rapidly dividing cells. The drug primarily affects tissues with high cellular turnover, such as cancer cells, skin, mucosal linings, bone marrow, fetal tissue, and bladder epithelium. Since malignant cells tend to proliferate more aggressively than normal cells, trimetrexate can target tumors while sparing most healthy tissues from permanent harm. However, because of its potential for severe and life-threatening toxicity, it must be administered alongside leucovorin for at least 72 hours after the final dose to protect normal cells. 

Pharmacokinetics 

Absorption 

The absorption of trimetrexate has not been established, as data on oral bioavailability is not available. 

Distribution 

Trimetrexate demonstrates a volume of distribution of approximately 20 ± 8 L/m² in the general population and 36.9 ± 6 L/m² in cancer patients. It is highly protein-bound (about 95%) within the plasma concentration range of 18.75 to 1000 ng/mL, indicating extensive distribution in body tissues. 

Metabolism 

The drug undergoes hepatic metabolism, with oxidative O-demethylation identified as the primary metabolic pathway. The resulting metabolites are further conjugated to either glucuronide or sulfate forms. 

Elimination/Excretion 

Between 10% and 30% of the administered dose is excreted unchanged in the urine, suggesting both renal and hepatic routes of elimination. 

Half-life: The elimination half-life of trimetrexate ranges from 11 to 20 hours, supporting once-daily dosing in clinical use. 

Clearance: Clearance varies by patient population and regimen: 38 ± 15 mL/min/m² in AIDS patients treated for Pneumocystis carinii pneumonia or toxoplasmosis 

53 ± 41 mL/min/m² in cancer patients receiving a single intravenous dose (10–130 mg/m²) 

30 ± 8 mL/min/m² in cancer patients after a five-day infusion 

Pharmacodynamics 

Trimetrexate is a synthetic, non-classical folate antagonist that inhibits dihydrofolate reductase (DHFR), an enzyme essential for converting folic acid to its active form, tetrahydrofolate, which is needed for DNA synthesis and cell division. By blocking this process, it disrupts the replication of rapidly dividing cells, such as cancer cells, skin and mucosal tissues, bone marrow, fetal cells, and urinary bladder cells. Because malignant cells divide more quickly than normal cells, trimetrexate can selectively target tumors with less harm to healthy tissues. However, due to its potential for severe and life-threatening side effects, it must be administered alongside leucovorin for at least 72 hours following the final dose to protect normal cells. 

Adminstartion

Route: Intravenous (IV) infusion only 

Dosage for PCP: Typically 45 mg/m²/day IV for 21 days + leucovorin rescue (20 mg orally every 6 hours, continuing for 72 hours after the last trimetrexate dose) 

Monitor CBCs and LFTs at least 2–3 times weekly 

Premedication not routinely required but monitor for hypersensitivity 

Patient Information Leaflet

Generic Name: Trimetrexate Glucuronate 

Pronunciation: trye-MET-rex-ate glue-KYOOR-oh-nate 

Why do we use Trimetrexate Glucuronate? 

Trimetrexate glucuronate is primarily used to treat moderate to severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, particularly those with AIDS, who are intolerant to or unresponsive to standard therapies like trimethoprim-sulfamethoxazole. Additionally, it is under investigation for potential use in treating certain cancers, such as leiomyosarcoma and pancreatic adenocarcinoma.